Pharmaceutical compositions which contain peptides or proteins as active ingredients present difficulties for oral administration since the active ingredients are attacked by the digestive system. Because oral administration is therefore tricky, and administration by injection is uncomfortable and presents a psychological barrier as well as some physiological risk, alternative means to administer these drugs have been sought.
Transfer of the drugs across a dermal layer or a mucosal membrane has been attempted. Transdermal administration is generally and logically fairly difficult as the function of the skin is to exclude substances from the interior of the organism. On the other hand, mucosal membranes are adapted to some level of absorption. Mucosal membranes are found, generally, in the digestive tract and in the respiratory system. It has therefore been possible in some instances to use either suppositories or nasal sprays as a method to deliver drugs systemically.
It is by now well known that bile salts are capable of enhancing the absorption of peptides, such as insulin and other drugs, across the nasal mucous membrane and across the rectal and vaginal mucous membranes (Duchateau, G.S.M.J.E. et al, in "Studies on Nasal Drug Delivery" (1986) Thesis:University of Amsterdam, pp. 87-98, citing Collens, W.S. et al, Proc Soc Exp Biol & Med (1932) 29:756-758; Toultou, E., et al, J Pharm Pharmacol (1978) 30:662-663 and a variety of other references). More recently, it has been shown that compositions containing a biocompatible, water soluble, amphiphilic steroid such as a fusidic acid derivative or a cephalosporin P derivative are also thus effective (Carey et al, U.S. Pat. No. 4,548,922 issued 22 Oct. 1985).
The use of nonionic detergents as carriers for the transmucosal administration of various drugs is also known. For example, British patent No. 2,127,689 to Sandoz claims a calcitonin composition which relies, for its ability to transport the active ingredient across the mucosal membrane, on an effective amount of a nonionic detergent which is a polyalkylene oxide derivative. In addition, polyacrylic acid gels have been used for nasal absorption of insulin and calcitonin by Morimoto, K., et al, J Pharm Pharmacol (1985) 37:134-136. U.S. Pat. No.4,153,689, assigned to Takeda describes an insulin nasal composition using Tween or polyoxyethylene-9-lauryl ether.
Sporadic reports of mixtures of carrier materials have also appeared. Muranishi, S., in Pharmaceutical Research (1985) pp. 108-118 describes monolein/bile salt mixed micelles as carriers which enhance the intestinal absorption of heparin. Oleic acid is also disclosed as useful in combination with a bile salt.
British Patent No. 1,527,605 to Takeda describes nasal administration of insulin with an adjuvant which is either a polyoxyethylene-9-lauryl ether or sodium glycocholate. While the specification casually indicates that mixtures of these excipients may be used, mixtures are not exemplified, nor is it clear what mixtures the disclosure intends to encompass. In addition, EPO Publication No. 0111847 to Syntex discloses the use of polysorbates mixed with bile salts for the administration of LHRH. Again, the specific features of this mixture are not identified, and the focus of the disclosure is on the utility of the bile salt.
Thus, although the use of bile salts with other detergents has been alluded to in these references in a general way, the inclusion of these additional surfactants in the carrier has been proposed as the inclusion of a harmless ingredient rather than a component which would change the characteristics (for better or worse) or the permeation capabilities of the bile salt composition with respect to the drug. To Applicants' knowledge there are no disclosures at all of administration of drugs using fusidates in admixture with nonionic detergents.
It has now been found that mixtures of bile salts or fusidates or their derivatives with nonionic detergents which are related to polymerized alkylene glycols or oxides provide compositions which have equivalent or increased permeation ability and lower toxicity compared to compositions containing corresponding amounts of bile salt or fusidate excipient alone.